Nucleophilic Acyl Substitution Reactions of Carboxylic Derivatives Flashcards
What are the major steps of all nucleophilic acyl substitution reactions?
1st major step = Nucleophilic attack of the carbonyl grp carbon to produce the alkoxide intermediate
2nd step = Elimintation of the leaving grp; producing new carbonyl compound
NOTE: There may be a step before the nucleophilic attack to alter the carboxy. acid derivative to be more electrophilic (reactive)
How does NU acyl substitution rxn differ from NU add. rxn?
1st major step = SAME (nucleophilic attack to produce alkoxide)
Following steps = DIFFERENT
–> NU add. rxn = Alkoxide ion protonates to yield alcohol
–> NU acyl sub. rxn. = Alkoxide ion undergoes elimination of the LG to yield new carbonyl compound
What determines reactivity of a compound in NU acyl sub. rxn?
The reactivity of the carbonyl carbon! Influenced by:
1) Steric hindrance around the carbonyl carbon (branching on the alpha carbons)
2) Electronics; Electrophilic nature of the carbonyl carbon
What is the rate limiting step of the NU acyl sub. rxn?
The nucleophilic attack of the carbonyl carbon
Greater branching on the alpha carbons of carboxylic acid derivatives =…
LESS REACTIVE in Nu acyl sub rxns.
Relationship between alpha-carbon branching and reactivity in Nu. acyl sub rxns?
Quarternary alpha-carbon (LEAST reactive)
<
Tertiary alpha-carbon
<
Secondary alpha-carbon
<
Primary alpha-carbon (MOST reactive)
What affects electrophilic character of the carbonyl carbon?
What is the relationship to reactivity in Nu. acyl sub rxns?
The groups bonded to the carbonyl carbon
–> EDGs will decrease E+ character = Decreases reactivity
–> EWGs will increase E+ character = Increases reactivity
Relative ranking of reactivity of carboxy. acid derivatives in Nu. acyl sub rxns
MOST Reactive to LEAST reactive:
1) Acyl Halides (most)
2) Acid Anhydrides
3) Thioesters
4) Esters
5) Amides (least)
ALL carboxy. acid derivatives can. be produced from carboxylic acids via…
BUT what must occur first?
Nucleophilic Acyl Substitution Reactions
BUT the OH grp is a poor LG so alterations must be made to make the carboxy. acid MORE reactive to nucleophile
What are the two main types of alterations to carboxy. acids to increase reactivity to nucleophile?
1) PROTONATION of the carbonyl oxygen to give a (+) charge to the carbonyl grp = increases E+ character!
–> Protonation typically mediated by a strong acid catalyst
2) Conversion of OH to a BETTER LG
Carboxylic Acid to Acyl Halide: Reactants
For Acyl Chloride:
SOCl2
———->
CHCl3
For Acyl Bromide:
PBr3
———->
ether
Carboxylic Acid to Acyl Chloride: General mechanism steps:
1) SOCl2 binds to the oxygen on the OH grp of the carboxylic acid, releasing Cl-
== SO2Cl bound to the carbonyl grp which is a better LG than the original OH
2) Free Cl- does nucleophilic attack on the carbonyl carbon
3) Oxygen electrons push down to eliminate SO2 from the carbonyl grp
== Acyl chloride!
Carboxylic Acid to Ester: Reactants
FISCHER ESTERIFICATION:
H2SO4 or HCl
————————->
ROH
Fischer Esterification (carboxylic acid to ester) PROCESS
PATED!
1) Protonation of the carbonyl oxygen by the acid
2) Attack of the nucleophile (ALCOHOL) to the carbonyl carbon
3) Transfer of a proton (H+) from (+) ROH to the OH grp to form OH2+
4) Elimination of OH2 (alleviating the + charge on the OH2)
–> Does so bY pushing electrons from the previously carbonyl oxygen (now an OH), reforming the carbonyl double bond
5) Deprotonation of the carbonyl oxygen by the acid catalyst conjugate base to alleviate the (+) charge
== Yields the ester! (and reforms the acid catalyst)
What are the two potential methods for:
Carboxylic Acid —> AMIDE
1) Form ACYL HALIDE and then react with an AMINE
2) React carboxylic acid with DCC and then with an AMINE
–> BOTH methods involve converting the OH grp to a better LG before reacting with the amine!
Carboxylic Acid to AMIDE via acyl halide: Reactants
1. SOCl2, CHCl3
——————————->
2. AMINE (< tertiary)
Carboxylic Acid to AMIDE via acyl halide: Process
1) Carboxylic acid reacts with SOCl2 to yield an acyl chloride
2) The amine (that is less than tertiary) attacks the carbonyl carbon of the acyl chloride
3) Free amine in solution then deprotonates the added amine to get rid of the (+) charge
4) Electrons from the alkoxide (-) push down to reform the carbonyl double bond AND eliminate (push off) the chlorine group
== AMIDE formed!
Carboxylic Acid to AMIDE with DCC: Reactants
1. DCC
—————————–>
2. AMINE (< tertiary)
Carboxylic Acid to AMIDE with DCC: Process
1) Carboxylic acid reacts with DCC; bonds to the oxygen of the OH grp to form a NEW and better LG!
2) Amine attacks the carbonyl carbon on the DCC sub. compound
3) Alkoxide electrons push down to reform carbonyl double bond and push off the DCC LG as DCU!
4) The pushed off DCC derivative deprotonates the added amine to get rid of the (+) charge on it
== AMIDE formed!
What are the reactions that acyl halides undergo (not including making them)?
SIX main reactions:
1) Hydrolysis: Acyl halide —-> Carboxylic Acid
2) Alcoholysis: Acyl halide —-> ESTER
3) Aminolysis: Acyl halide —-> AMIDE
4) Grignard: Acyl halide —> 3° alcohol!
5) FULL Reduction: Acyl halide —> 1° alcohol
6) PARTIAL Reduction: Acyl halide —> ALDEHYDE
Acyl Halide Hydrolysis: Reactants
Acyl Halide (RCOX) —-> Carboxylic Acid (RCOOH)
H2O
———————–>
Base? (to prevent excessive halide acid formation)
Acyl Halide Hydrolysis: Process
1) Acyl halide carbonyl carbon is attacked by WATER = sub. alkoxide
2) Alkoxide electrons push down to reform carbonyl double bond AND push off the halide LG (X)!
3) Base or X- deprotonates the H2O+ on the carbonyl
== carboxylic acid!
Acyl Halide Alcoholysis: Reactants
Acyl halide —-> ESTER
ROH (alcohol)
———————————>
Et3N (tertiary amine base!)
Acyl Halide Alcoholysis: Process
1) Alcohol (ROH) acts as nucleophile and attacks the carbonyl carbon of the acyl halide = alkoxide forms
2) The alkoxide pushes electrons down to reform carbonyl double bond AND push off the halide LG
3) Et3N deprotonates the added ROH+ grp on the carbonyl
== ESTER forms!
How does substitution of the alcohol affect acyl halide alcoholysis?
The LESS SUBSTITUTED the alcohol, the more reactive it is!
Ex: If a molecule has a 2° and a 1° alcohol, the 1° OH will undergo alcoholysis to form an ester because it is more reactive!
Most reactive = 1° ROH —–> 3°ROH (LEAST reactive!)
Acyl halide Aminolysis: Reactants
Two potential methods:
2 eq. (AMINE, <3°)
——————————–>
or
AMINE (< 3°)
—————————->
Et3N
Acyl halide Aminolysis: Process (for both methods)
1) Amine acts as nucleophile and attacks the carbonyl carbon
2) Alkoxide electrons push down to reform carbonyl DB and to push off (eliminate) halide LG
3) Deprotonation: mechanism depends on base present!
–> If 2 eq. amine were used:
second equivalent of amine will come and deprotonate the first added amine to resolve the (+) charge and produce the amide
–> If 1 eq. of amine + Et3N were used:
Et3N will deprotonate the added amine to resolve the (+) charge and produce the amide
Acyl halide + Grignard: Reactants
Acyl halide —-> 3° Alcohol!
1. 2 eq. GRIGNARD (RMgX)
—————————————->
2. H3O+
Acyl halide + Grignard: Process
Reaction happens TWICE!
Rxn 1:
1) ONE grignard reagent does Nu attack to the carbonyl carbon of the acyl halide = Alkoxide forms with R grp from grignard
2) Alkoxide electrons push down to reform carbonyl DB and kick off the halide LG
== KETONE is formed! (Intermediate)
Rxn 2:
3) Formed ketone is immediately attacked by the SECOND grignard reagent at the carbonyl carbon = Alkoxide forms with a second R grp from grignard
4) Alkoxide is protonated by the H3O+ (CANT push down to form DB as the carbon is now 4°!)
== 3° alcohol (with two identical R groups from the grignards!)
Acyl halide FULL reduction: Reactants
Acyl halide —-> 1° alcohol!
1. LiAlH4
————————–>
2.H3O+
Acyl halide FULL reduction: Process
Rxn. occurs TWICE:
Rxn 1:
1) H- of Li+AlH4- attacks the carbonyl carbon = alkoxide forms
2) Alkoxide electrons push down to reform carbonyl DB and push off the halide LG
== ALDEHYDE forms! (Intermediate)
Rxn 2:
3) Aldehyde immediately gets attacked at carbonyl carbon by H- of more Li+AlH4- = forms alkoxide
4) Alkoxide is PROTONATED by H3O+
(Alkoxide electrons CANT push down to reform carbonyl DB because the carbon is now 4°!)
== 1° alcohol forms!
(with two Hs on previously carbonyl carbon from LiAlH4)
Acyl Halide PARTIAL Reduction: Reactants
Acyl halide —-> KETONE
R2CuLi
—————–>
Dialkylcopper lithium reagent = GILMAN reagent!
May also see as:
(CH3CH2)2CuLi
Acyl Halide PARTIAL Reduction: Process
1) The copper of the dialkyl copper (R2Cu) portion of the gilman reagent replaces halide on the acyl halide
2) RCu leaves and one of the R groups stays behind, bound to the carbonyl carbon
== KETONE is formed!
Reactions of acid anhydrides:
Undergo almost ALL the same reactions as acyl halides BUT just slower (because they are less reactive):
1) Hydrolysis (Anhydride –> 2x carboxylic acid)
2) Aminolysis (Anhydride –> Amide + carboxylate ion)
3) Alcoholysis (Anhydride —> Ester + carboxylate ion)
4) Grignard (Anhydride —> 2x 3° alcohol!)
5) FULL reduction (Anhydride —> 2x 1° alcohol!)
(DOES NOT do partial reduction! Gilman reagents only work with acyl halides!)
Anhydride Hydrolysis: Reactants + Process
Anhydride —> 2x Carboxylic Acids
H2O
————–>
1) H2O acts as nucleophile and attacks ONE of the carbonyl carbons = Alkoxide forms
2) Electrons of alkoxide push down to reform carbonyl grp and kick off a carboxylate ion
3) Carboxylate ion deprotonates H2O+ on the other carbonyl carbon
== Forms TWO carboxylic acids (will be identical if the anhydride was symmetrical)
Anhydride FULL reduction: Reactants + Process
Anhydride —> 2x 1° alcohols
1. LiAlH4
————————–>
2.H3O+
1) First reduction occurs to yield an aldehyde and a carboxylate ion (which can protonate to carboxylic acid)
2) BOTH the carboxylic acid and the aldehyde are immediately reduced and then the alkoxide is protonated on both to yield TWO 1° alcohols!
Anhydride + Grignard: Reactants + Process
Anhydride —> 2x 3° alcohols
1. 4x GRIGNARD (RMgX)
—————————————->
2. H3O+
1) First grignard reaction produces ONE ketone and one carboxylate ion
2) Second round of grignard reactions produces ONE 3° alcohol and ONE ketone
3) Last grignard reaction turns the remaining ketone into a 3° alcohol
== TWO 3° alcohols!
Anhydride Alcoholysis: Reactants + Process
Anhydride —> ONE ester + ONE carboxylate ion
ROH (alcohol)
———————————>
Et3N (tertiary amine base!)
1) Alcohol does Nu attack at ONE of the carbonyl carbons = alkoxide forms
2) Formed alkoxide pushed electrons down to reform carbonyl DB and kick off a carboxylate ion
3) Et3N deprotonates the ROH+ to give the ESTER
== ESTER + carboxylate ion
Anhydride Aminolysis: Reactants + Process
Anhydride —> ONE amide + ONE carboxylate ion
Amine, <3°
——————————>
Et3N (tertiary amine base!)**
1) Amine does Nu attack at ONE of the carbonyl carbons = alkoxide forms
2) Alkoxide electrons push down to reform carbonyl DB and kick off a carboxylate ion
3) Et3N deprotonates the added Amine+ to give the AMIDE
== AMIDE + carboxylate ion
What are the methods in which esters can be MADE?
1) FISCHER ESTERIFICATION (carboxylic acid + ROH + ACID CAT)
2) Acyl halide alcoholysis (acyl halide + ROH + Et3N)
NOT usually used:
3) Base hydrolysis followed by alkyl halide attack
(Carboxylic acid + NaOH + 1°RX)
–> Carboxylic acid is converted to carboxylate ion via hydroxide (base) –> RCOO- then attacks a PRIMARY alkyl halide to form ester (SN2 like mechanism)
Why is base hydrolysis + alkyl halide attack not preferred for ester preparation?
Because it is limited in the esters it can make!
The R grp that gets attached to the bridge carbon can only be PRIMARY as the alkyl halide used to make it must be primary!
Ester Reactions:
Can undergo 6 reactions:
1A) Acid-catalyzed hydrolysis (RCOOR —> Carboxylic acid + ROH)
1B) Base-induced hydrolysis (RCOOR —> Carboxylic acid + ROH)
2) Aminolysis (RCOOR —> Amide + ROH)
3) FULL Reduction (RCOOR —-> 1° alcohol + ROH)
4) PARTIAL Reduction (RCOOR —> Aldehyde + ROH)
5) Grignard rxn. (RCOOR —> 3° alcohol + ROH
Ester Acid-Catalyzed Hydrolysis: Reactants
RCOOR —> Carboxylic acid + byproduct ROH
H2SO4
———————>
**H2O
Ester Acid-Catalyzed Hydrolysis: Process
1) H2SO4 protonates the carbonyl oxygen = gives (+) charge to the ester
2) H2O acts as nucleophile and attacks carbonyl carbon (DB electrons push up to form stable OH grp)
3) Proton transfer: H+ transfers from the added H2O+ to the bridge oxygen (-OR grp) to create ROH+ LG!
4) Electrons from oxygen in one of the two OH grps push down to reform carbonyl DB and pushes off ROH!
5) HSO4- deprotonates the protonated carbonyl oxygen
== Carboxylic Acid + ROH byproduct!
Ester Base-Induced Hydrolysis: Reactants
RCOOR —> Carboxylic acid + byproduct ROH
NaOH
—————–>
H2O (just there to solubilize NaOH)
Ester Base-Induced Hydrolysis: Process
1) OH- of NaOH attacks carbonyl carbon as a nucleophile = alkoxide forms
2) Alkoxide electrons push down to reform carbonyl DB and push off OR-
= Carboxylic acid is formed!
3) Free OR- is very basic and deprotonates the acidic OH on the formed carboxylic acid (acid-base rxn)
== Carboxylate ion + ROH byproduct
NOTE: Must hit with acid to reprotonate the carboxylate ion to get the carboxylic acid
Ester Aminolysis: Reactants
Ester —> AMIDE + ROH
Amine, <3°
—————–>
Ester Aminolysis: Process
1) Amine acts as nucleophile and attacks carbonyl carbon = alkoxide forms
3) Alkoxide electrons push down to reform carbonyl DB and pushes off OR-
3) Free OR- deprotonates the added amine+ to remove the (+) charge
==AMIDE formed! + ROH byproduct
Ester FULL Reduction: Reactants
Ester —> 1° alcohol + ROH
1. LiAlH4
————————–>
2.H3O+
Ester FULL reduction: Process
TWO reductions occur:
Rxn 1:
1) AlH4- attacks the carbonyl carbon of the ester = alkoxide forms
2) Alkoxide pushes down electrons to reform carbonyl DB and pushes off OR-
== ALDEHYDE forms + OR- byproduct (gets protonated later to produce ROH
Rxn. 2:
3) Aldehyde gets immediately reduced by LiAlH4 again to yield an alkoxide
4) Alkoxide is protonated by H3O+
== 1° alcohol + ROH byproduct
Ester PARTIAL Reduction: Reactants
Ester —-> Aldehyde + ROH
1. DIBAH or i-Bu2Al-H, -78C in hexane
———————————————————->
2.H3O+
DIBAH = Diisobutylaluminum hydride
Ester PARTIAL Reduction: Process
1) DIBAH acts as H- source to form the aldehyde
2) Acid is used to protonate the OR- to give the byproduct ROH
== ALDEHYDE + byproduct ROH
Ester + Grignard Reagent: Reactants
Ester —> 3° alcohol + ROH
1. 2x GRIGNARD (RMgX)
—————————————->
2. H3O+
What conditions are needed for partial reduction using DIBAH in esters?
1) Organic solvent (Like toluene or hexane)
2) -78°C
Ester + Grignard Reagent: Process
Rxn happens TWICE:
1) One grignard reacts with the ester to produce a KETONE + OR-
2) Ketone immediately reacts with second grignard to produce an alkoxide compound
3) Alkoxide is protonated by acid to yield the 3° alcohol (and OR- from the first grignard reaction is protonated to yield ROH byproduct)
== 3° alcohol + ROH byproduct
What are the methods of MAKING amides?
TWO main methods:
1) Acyl halide aminolysis (acyl halide + Amine (<3°) + Et3N)
2) Carboxylic acid and DCC! (carboxy acid + DCC + Amine (<3°))
(No extra base needed)
Amide Reactions:
Undergo THREE main reactions:
1A) Acid-Catalyzed Hydrolysis (Preferred) (amide –> RCOOH + amine)
1B) Base-Induced Hydrolysis (amide —> RCOO- + amine)
2) FULL Reduction (Amide –> AMINE)
(NO mechanism for partial reduction)
(NO reaction with grignard!)
Amide Acid-Catalyzed Hydrolysis: Reactants
Amide —> Carboxylic acid + Amine
H3O+
—————->
H2O
Amide Acid-Catalyzed Hydrolysis: Process
1) Carbonly oxygen of the amide protonates from the acid = gives amide a (+) charge (attracts Nu)
2) H2O acts as nucleophile and attacks the carbonyl carbon and pushes the DB electrons up to form a stable OH grp
3) PROTON TRANSFER: Nitrogen of the nitro grp. gets protonated by taking H+ from the added H2O+
4) Electrons from OH grp push down to reform carbonyl DB and push off the protonated nitro grp = releases an AMINE
5) H2O deprotonates the carbonyl oxygen to get rid of the (+) charge and produce the carboxylic acid!
== Carboxylic acid + AMINE
Amide Basic Hydrolysis: Reactants
Amide —> Carboxylate ion + Amine
NaOH
—————->
H2O (just to solubilize NaOH)
Amide Basic Hydrolysis: Process
1) Hydroxide acts as nucleophile and attacks the carbonyl carbon = forms alkoxide
2) Alkoxide pushes electrons down to reform carbonyl DB and pushes off a (-) amine grp == Forms carboxylic acid!
3) The (-) amine grp comes back and deprotonates the OH grp of the carboxylic acid (acid-base rxn)
== Carboxylate ion + AMINE
Amide FULL Reduction: Reactants
Amide —-> Amine
1. LiAlH4
————————–>
2.H3O+
Amide FULL reduction: Process
Involves two reduction steps!
Rxn 1:
1) H- attacks the carbonyl carbon to form alkoxide
–> which immediately reacts with AlH3 to form an OAlH3 leaving group!
2) Electrons from nitrogen of the nitro grp push down to form DB with carbonyl carbon and in this process pushes off the OAlH3 leaving group
==IMMINIUM ION forms (nitro group has a + charge)
Rxn 2:
3) H- attacks imminium ion at the nitro CARBON, pushing the ntiro DB electrons UP to the nitro group
= gets rid of the (+) charge and the amine is formed!
== AMINE formed!
